{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Mitochondrial ferredoxin 2 (FDX2) has emerged as a specialized electron‐carrier that is essential for the biogenesis of iron–sulfur (Fe/S) clusters and heme A, thereby supporting the maturation of critical mitochondrial proteins. Unlike its paralog FDX1—which primarily facilitates electron transfer to cytochrome P450 enzymes in steroidogenesis—FDX2 specifically interacts with the cysteine desulfurase complex and scaffold proteins to drive the reductive assembly and fusion of [2Fe–2S] clusters into functional Fe/S centers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In vitro studies demonstrate that FDX2 binds more tightly to the cluster‐assembly machinery and supports a faster rate of cluster formation than FDX1, a property that is linked to its distinct conformational dynamics and substrate specificity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Genetic and clinical investigations further highlight the non‐redundant role of FDX2: mutations in the FDX1L gene (encoding FDX2) are associated with mitochondrial myopathy, episodic rhabdomyolysis, and complex neurological syndromes, underscoring its critical in vivo function in Fe/S protein maturation and cellular iron homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": " Moreover, electron transfer from FDX2 has been shown to be indispensable in mediating the reductive fusion step required for the generation of [4Fe–4S] clusters, a role that cannot be compensated by other reducing systems or by FDX1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Beyond its physiological significance, FDX2 can also serve as an effective redox partner in specific cytochrome P450 systems, highlighting its potential utility in biotechnological applications."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these studies establish FDX2 as a distinct, non‐redundant mitochondrial ferredoxin that is vital for Fe/S cluster assembly, mitochondrial energy metabolism, and maintenance of cellular iron balance.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alex D Sheftel, Oliver Stehling, Antonio J Pierik, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1004250107"}], "href": "https://doi.org/10.1073/pnas.1004250107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20547883"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20547883"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yanbo Shi, Manik Ghosh, Gennadiy Kovtunovych, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Both human ferredoxins 1 and 2 and ferredoxin reductase are important for iron-sulfur cluster biogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamcr.2011.11.002"}], "href": "https://doi.org/10.1016/j.bbamcr.2011.11.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22101253"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22101253"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kai Cai, Marco Tonelli, Ronnie O Frederick, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FDX2) Both Bind Cysteine Desulfurase and Donate Electrons for Iron-Sulfur Cluster Biosynthesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/acs.biochem.6b00447"}], "href": "https://doi.org/10.1021/acs.biochem.6b00447"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28001042"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28001042"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Wenbin Qi, Jingwei Li, J A Cowan "}, {"type": "b", "children": [{"type": "t", "text": "Human ferredoxin-2 displays a unique conformational change."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dalton Trans (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1039/c2dt32018e"}], "href": "https://doi.org/10.1039/c2dt32018e"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23208207"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23208207"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ronen Spiegel, Ann Saada, Jonatan Halvardson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2013.269"}], "href": "https://doi.org/10.1038/ejhg.2013.269"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24281368"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24281368"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Juliana Gurgel-Giannetti, David S Lynch, Anderson Rodrigues Brandão de Paiva, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel complex neurological phenotype due to a homozygous mutation in FDX2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awy172"}], "href": "https://doi.org/10.1093/brain/awy172"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30010796"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30010796"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Anjali Aggarwal, Nishitha R Pillai, Charles J Billington, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rare presentation of FDX2-related disorder and untargeted global metabolomics findings."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.62608"}], "href": "https://doi.org/10.1002/ajmg.a.62608"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34905296"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34905296"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Benjamin Dennis Weiler, Marie-Christin Brück, Isabell Kothe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial [4Fe-4S] protein assembly involves reductive [2Fe-2S] cluster fusion on ISCA1-ISCA2 by electron flow from ferredoxin FDX2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.2003982117"}], "href": "https://doi.org/10.1073/pnas.2003982117"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32817474"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32817474"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Holger Webert, Sven-Andreas Freibert, Angelo Gallo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional reconstitution of mitochondrial Fe/S cluster synthesis on Isu1 reveals the involvement of ferredoxin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms6013"}], "href": "https://doi.org/10.1038/ncomms6013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25358379"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25358379"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Mohammed Milhim, Natalia Putkaradze, Ammar Abdulmughni, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a new plasmid-encoded cytochrome P450 CYP107DY1 from Bacillus megaterium with a catalytic activity towards mevastatin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biotechnol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jbiotec.2016.11.002"}], "href": "https://doi.org/10.1016/j.jbiotec.2016.11.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27816653"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27816653"}]}]}]}